4. Angiotensinogen (Liver) Renin (kidney) Angiotensin I Non ACE Pathway ACE Pathway Angiotensin II AT1 receptors AT2 receptors Increase Aldosterone. Increase Na + and H 2 O retention. Increase Venous return. Increase Preload Increase Stimulation of SNS. Thus heart rate and CO Increase Increase Cell growth Physiology of RAAS Increase Vasoconstriction ( PVR)
5. Inappropriate RAAS Activation as a Cause of Impaired Vascular and Metabolic Health Angiotensin II Atherosclerosis Impaired Adipogenesis Elevated BP Endothelial Dysfunction Vascular Remodeling Glucose Intolerance Brasier et al. Arterioscler Thromb Vasc Biol. 2002;22:1257-1266; Dzau. J Hypertens. 2005;23(suppl 1):S9-S17; Engeli et al. Int J Biochem Cell Biol. 2003;35:807-825; Taniyama et al. Hypertension. 2003;43:1075-1081.
6. Angiotensin II effect in target organ damage McFarlane SI et al. Am J Cardiol . 2003;91(suppl):30H-7. Angiotensinogen Angiotensin I Angiotensin II Renin ACE Aldosterone (Adrenal/CV tissues) Stroke HF Kidney failure BP VSMC Fat cells Reduced baroreceptor sensitivity
7. Angiotensin II as a Cardiac and Renal Toxin Chymase Cathepsin G Carboxypeptidase Reactive O 2 Species Cell Growth Renal Na + , H 2 O Collagen Sympathetic Activation Aldosterone Vasoconstriction CHF Cardiac, Vascular, Renal Hypertrophy Bradykinin Inactive Fragments Ang II Ang I Angiotensin Renin AT 1 R Carey et al. Endocr Rev . 2003;24:261-271 .
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9. Potential role of RAAS activation in metabolic syndrome and diabetes Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9. Paul M et al. Physiol Rev. 2006;86:747-803. RAAS activation Skeletal muscle Pancreatic β cells MetS T2DM MetS = metabolic syndrome T2DM = type 2 diabetes Obesity
14. Angiotensinogen (Liver) Renin (kidney) Angiotensin I Non ACE Pathway ACE Pathway Angiotensin II AT1 receptors AT2 receptors Increase Aldosterone. Increase Na + and H 2 O retention. Increase Venous return. Increase Preload Increase Stimulation of SNS. Thus heart rate and CO Increase Increase Cell growth RAAS Modulators Increase Vasoconstriction ( PVR) ACE’s ARB’s Direct Renin Inhibitors MECHANISM OF ACTION
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18. Development of ARB’s Became the first successful Ang II antagonist drug Valsartan –nonheterocyclic ARB Candesartan – Prodrug have stronger blood pressure lowering effects than and losartan. Irebesartan - longer acting than valsartan & losartan Telmisartan - longest elimination half-life of the ARBs or about 24 hours Olmesartan - Newest ARB on the market, marketed in 2002
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20. AT 1 affinity The specific AT1 affinity relates to how specificially attracted the medicine is for the correct receptor. http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist#AT1_affinity valsartan > olmesartan > candesartan > Irbesartan > telmisartan > losartan * * Andrew Whittaker .A Review of Olmesartan Medoxomil -- A New Angiotensin II Receptor Blocker . Br J Cardiol. 2005;12(2):125-129.
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22. Drug comparison and pharmacokinetics 1. Sankyo Pharma Inc (US). Expanding the Paradigm for Hypertension Management with a New Angiotensin II Receptor Blocker. Benicar® (Olmesartan Medoxomil) [product monograph]. New York: Advantage Communications, 2002. 2. Olin BR, ed. Drug Facts and Comparisons. St. Louis: JB Lippincott Co, 2002:514–518.
23. Dosing schedule* (QD indicates once a day; BID, twice a day) *Olin BR, ed. Drug Facts and Comparisons. St. Louis: JB Lippincott Co, 2002:514–518. * Burnier M. Angiotensin II type 1 receptor blockers. Circulation 2001;103:904– 912. † Some patients will require the total daily dose to be split into twice-daily dosing
24. ARB in Reducing BP and CV events 1. Dahlöf B, Devereux RB, Kjeldsen SE et al . Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003. 2. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60. Name Patient population Drugs/follow up Results LIFE 1 (Losartan Intervention For Endpoint Reduction in Hypertension Study) 9,193 patients aged 55-80 yr with hypertension and LVH Losartan, 50-100 mg qd, vs atenolol, 50-100 mg qd Mean follow-up: 4.8 yr Losartan decreased the composite end point (cardiovascular mortality, MI, and stroke), stroke, and new-onset diabetes significantly more than atenolol for a similar reduction in blood pressure OPTIMAAL 2 (Optimal Trial In Myocardial Infarction with the Angiotensin Receptor Blocker Losartan) 5,477 European patients aged over 50 with confirmed acute MI and heart failure. Losartan, 50 mg qd, vs captopril, 50 mg tid Mean follow-up: 2.7 yr No significant difference in overall mortality between the groups. The ARB was better tolerated than the ACE inhibitor, with significantly fewer withdrawals due to adverse effects.
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27. ARB’s in AMI & Heart Failure 1. Pfeffer et al., N Engl J Med 349(20):1893-1906 November 13, 2003. 2.Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345: 1667-75. Name Patient population Drugs/follow up Results VALIANT (VALsartan In Acute myocardial iNfarcTion) 14,703 patients aged > 18 yr with acute MI complicated by left ventricular dysfunction or heart failure Valsartan, 160 mg bid, vs captopril, 50 mg tid, vs valsartan, 80 mg bid, plus captopril, 50 mg tid Median follow-up: 24.7 mo Valsartan was as effective as captopril at decreasing all-cause mortality and a composite of cardiovascular death, MI, and heart failure hospitalization ; combination of valsartan and captopril offered no additional benefit but increased the rate of adverse events Val-HeFT 5,010 patients aged > 18 yr with NYHA class II-IV heart failure Valsartan, 160 mg bid, vs placebo (open ACE inhibitor) Mean follow-up: 23 mo Valsartan significantly reduced mortality and morbidity and improved clinical signs and symptoms when added to prescribed therapy. An adverse effect on mortality and morbidity was observed in the subgroup receiving valsartan, an ACEI + beta-blocker
28. ARB’s in AMI & Heart Failure * Postgrad Med 2004;116(2):31-41 Name Patient population Drugs/follow up Results ELITE* 722 patients aged > 65 yr with NYHA class II-IV heart failure Losartan, 50 mg qd, vs captopril, 50 mg tid Losartan and captopril had similar effects on renal dysfunction (primary end point); all-cause mortality was significantly lower with losartan than captopril ELITE II* 3,152 patients aged > 60 yr with NYHA class II-IV heart failure Losartan, 50 mg qd, vs captopril, 50 mg tid Median follow-up: 79.3 wk Nonsignificant trend in favor of captopril for all-cause mortality, sudden death or resuscitated cardiac arrest, and a composite of all-cause mortality and hospitalization
37. ONTARGET: Study design ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61. Ramipril 10 mg Telmisartan 80 mg ≥ 55 years with coronary, Cerebrovascular, or peripheral vascular disease, or diabetes + end-organ damage Ramipril 10 mg + telmisartan 80 mg Primary end point: CV death, MI, stroke, hosp for HF Secondary end point: Newly diagnosed diabetes N = 25,620 Medical Services
38. ONTARGET: Primary outcome results N = 25,620 with vascular disease or high-risk diabetes ONTARGET Investigators. N Engl J Med .2008;358:1547-59. Cumulative hazard ratio 0.20 0.15 0.10 0.05 0.00 0 1 2 3 4 5 Follow-up (years) Telmisartan Ramipril Telmisartan plus ramipril
39. ONTARGET: Incidence of primary outcome and components ONTARGET Investigators. N Engl J Med . 2008;358:1547-59. Outcome Ramipril (n = 8576) Telmisartan (n = 8542) Combination (n = 8502) Telmisartan vs ramipril Combination vs ramipril Primary outcome 16.5% 16.7% 16.3% 1.01 RR (0.94–1.09) 0.99 RR (0.92–1.07) Death from CV causes 7.0% 7.0% 7.3% 1.00 RR (0.89–1.12) 1.04 RR (0.93–1.17) MI 4.8% 5.2% 5.2% 1.07 RR (0.94–1.22) 1.08 RR (0.94–1.23) Stroke 4.7% 4.3% 4.4% 0.91 RR (0.79–1.05) 0.93 RR (0.81–1.07) HF hospital-ization 4.1% 4.6% 3.9% 1.12 RR (0.97–1.29) 0.95 RR (0.82–1.10)
When examining the interaction between the RAAS and the SNS, it can be seen that both play an integral part in vascular adaptive processes. Hyperactivity of the SNS is known to stimulate the secretion of renin, which is the first component of the RAAS system. High levels of plasma renin activity (PRA) have been linked to metabolic imbalances such as hyperlipidemia and hyperinsulinemia, both of which are risk factors for CVD. When sympathetic activity is blocked in renin-dependent hypertension patients, it has been shown to inhibit RAAS activity. The heightened secretion of norepinephrine (NE) by the SNS has also shown a link to CVD. A large scale clinical trial demonstrated that NE levels of >900 pg/mL were correlated with shortened life expectancy in patients with severe congestive heart failure (CHF). Cody RJ. The sympathetic nervous system and the renin-angiotensin-aldosterone system in cardiovascular disease. Am J Cardiol . 1997;80:9J-14J.
The ON going T elmisartan A lone and in combination with R amipril G lobal E ndpoint T rial (ONTARGET) randomized 25,620 high-risk patients to telmisartan 80 mg, ramipril 10 mg, or their combination. Eligible subjects were ≥ 55 years of age with coronary, cerebrovascular, or peripheral vascular disease, or with diabetes plus evidence of end-organ damage. The primary end point is a composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for congestive heart failure. New-onset diabetes is one of the secondary end points. Patients will be followed for up to 5.5 years. Recruitment ended in 2003. ONTARGET: Study design
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